Core D: Neuropathology Core. Summary/Abstract: The Neuropathology (NP) Core fulfills several important roles within the University of Pittsburgh ADRC (PITT-ADRC). Postmortem neuropathological confirmation of the clinical diagnosis of Alzheimer?s disease (AD) and related disorders and the assessment of co-existing neurodegenerative and vascular disease processes is essential to promote progress in diagnosis, treatment and prevention of AD. Since its inception, the NP Core has collected and characterized >739 brains from PITT-ADRC subjects at various disease stages. This resource has been extensively utilized for teaching purposes and for research studies by local and national investigators to develop amyloid PET imaging agents and correlate in vivo amyloid imaging results with postmortem findings, improve our understanding of genetic factors contributing to AD risk and advance our knowledge regarding the neurobiology of psychiatric comorbidities and neuroinflammatory processes. Our proposed approach to fulfill the diagnostic, tissue banking, research and educational roles of the NP Core is outlined in five specific aims: 1) The NP Core will continue to maintain and expand a well-catalogued bank of brain tissue samples and fibroblasts of ADRC participants and subjects from affiliated cohorts. A special emphasis will be placed on harvesting brains from subjects with premortem PiB and tau PET imaging studies. 2) All banked cases will undergo detailed diagnostic evaluation using the latest consensus criteria and detailed characterization of comorbid and aging-related pathologies. Results will be shared with ADRC clinical staff, families and uploaded to local and national databases (NACC). 3) The NP Core will provide neuropathological skills and expertise to researchers and will expand its efforts to utilize digital microscopy technologies and image analysis tools for identification and quantification of neurodegenerative pathologies. The generated pathology endophenotypes will be made available for association studies with genetic polymorphisms and clinical phenotypes such as the presence of psychiatric comorbidities, a major area of research at the PITT-ADRC. 4) The NP Core will continue to participate in local and national research efforts by providing brain bank tissue materials and neuropathology data from diagnostic evaluations. The NP core will closely collaborate with other PITT-ADRC cores and projects in joint research studies and will engage in NP Core-driven research projects. 5) In collaboration with the Research Education Component, the NP core will leverage brain bank materials and expertise to educate neuropathology fellows, residents, medical students and investigators about the neuropathologic features of neurodegenerative diseases. Through these aims, the NP core will provide precise diagnostic classifications of ADRC research participants, enable studies of phenotype variations and broadly support efforts to improve our understanding of the underlying disease processes.